Genetic Determinants of Pemetrexed Responsiveness and Nonresponsiveness in Non-small Cell Lung Cancer Cells

Wu, Ming-Fang; Hsiao, Yi‐Min; Huang, Chin-Shiu; Huang, Yu‐Hsin; Yang, Wan-Jung; Chan, Hsiu‐Wen; Chang, Jinghua Tsai; Ko, Jiunn‐Liang

doi:10.1097/jto.0b013e3181e0b954

Cited by 41 publications

(32 citation statements)

References 27 publications

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“…Wu et al found downing stream of TS gene may serve as new biomarkers for predicting responsiveness to pemetrexed [13]. Similar results were also reported by Chiappori in small cell lung Figure 4 Subgroup analysis by chemotherapy regimen.…”

Section: Discussionsupporting

confidence: 75%

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The Pemetrexed-Containing Treatments in the Non-small Cell Lung Cancer, Is -/Low Thymidylate Synthase Expression Better than +/High Thymidylate Synthase Expression? A Meta-analysis

Wang

Pan

et al. 2014

Chest

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Background: The predictive value of thymidylate synthase (TS) for clinical sensitivity to pemetrexed-containing chemotherapy in patients with non-small cell lung cancer (NSCLC) remains controversial. This meta-analysis is performed to provide an assessment of whether expression variations of TS are associated with objective response in patients with NSCLC treated with pemetrexed-containing chemotherapy. Methods: An electronic search was conducted using the databases MEDLINE, EMBASE and CNKI, from inception to June 10 th , 2013. A systemic review of the studies on the association between TS expression in NSCLC and objective response of pemetrexed-containing regimen was performed. Pooled odds ratios (OR) for the response rate were calculated using the software Revman 5.0.Results: There were a total of 526 patients in the eight studies that met our criteria for evaluation. +/high expression of TS was found in 269 patients (51.1%), and -/low expression for this gene was found in 257 (48.9%) patients. The objective response rate for pemetrexed-containing chemotherapy was significantly higher in patients with -/low expression TS expression (OR = 0.45; 95% CI, 0.29-0.70; p = 0.0004). Although patients with -/low expression of TS have a longer median overall survival time and progression free survival time than those with +/high expression of TS, the difference was not statistically significant.Conclusions: −/low expression of TS was associated with higher objective response in NSCLC patients treated with pemetrexed-containing chemotherapy. TS may be a suitable marker of sensitivity to pemetrexed-based chemotherapy in patients with NSCLC.

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Section: Discussionsupporting

confidence: 75%

“…Among them, TS is a key enzyme that catalyzes the methylation of fluorod UMP, the precursor of DNA synthesis, into dTMP [13]. Recent in vitro studies demonstrated that lung cancer cell lines with low thymidylate synthase expression were highly sensitive to pemetrexed [14][15][16].…”

Section: Introductionmentioning

confidence: 99%

The Pemetrexed-Containing Treatments in the Non-small Cell Lung Cancer, Is -/Low Thymidylate Synthase Expression Better than +/High Thymidylate Synthase Expression? A Meta-analysis

Wang

Pan

et al. 2014

Chest

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“…An increasing number of studies have shown that elevated TS expression is associated with resistance to fluoropyrimidine-based therapy in colorectal cancer (16)(17)(18)(19)(20) and S-1 (21) and UFT (22) in NSCLC. Accumulating evidence also indicates that TS overexpression is a determinant of sensitivity to pemetrexed (23)(24)(25)(26)(27)(28)(29). However, benefits from TS-targeted chemotherapy in NSCLC seems to have plateaued, and their continued clinical success may depend on our ability to correctly administer these agents following biomarker-driven patient selection (30).…”

Section: Introductionmentioning

confidence: 99%

Inhibition of dUTPase Induces Synthetic Lethality with Thymidylate Synthase–Targeted Therapies in Non–Small Cell Lung Cancer

Wilson

LaBonte

Lenz

et al. 2012

Molecular Cancer Therapeutics

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Chemotherapies that target thymidylate synthase (TS) continue to see considerable clinical expansion in non-small cell lung cancer (NSCLC). One drawback to TS-targeted therapies is drug resistance and subsequent treatment failure. Novel therapeutic and biomarker-driven strategies are urgently needed. The enzyme deoxyuridine triphosphate nucleotidohydrolase (dUTPase) is reported to protect tumor cells from aberrant misincorporation of uracil during TS inhibition. The goal of this study was to investigate the expression and significance of dUTPase in mediating response to TS-targeted agents in NSCLC. The expression of dUTPase in NSCLC cell lines and clinical specimens was measured by quantitative real-time reverse transcriptase PCR and immunohistochemistry. Using a validated RNA interference approach, dUTPase was effectively silenced in a panel of NSCLC cell lines and response to the fluoropyrimidine fluorodeoxyuridine (FUdR) and the antifolate pemetrexed was analyzed using growth inhibition and clonogenic assays. Apoptosis was analyzed by flow cytometry. Significant variation in the quantity and cellular expression of dUTPase was observed, including clear evidence of overexpression in NSCLC cell line models and tumor specimens at the mRNA and protein level. RNA interference-mediated silencing of dUTPase significantly sensitized NSCLC cells to growth inhibition induced by FUdR and pemetrexed. This sensitization was accompanied by a significant expansion of intracellular dUTP pools and significant decreases in NSCLC cell viability evaluated by clonogenicity and apoptotic analyses. Together, these results strongly suggest that uracil misincorporation is a potent determinant of cytotoxicity to TS inhibition in NSCLC and that inhibition of dUTPase is a mechanism-based therapeutic approach to significantly enhance the efficacy of TS-targeted chemotherapeutic agents.

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“…23 Several studies have demonstrated that MTX (inhibitor of dihydrofolate reductase), AG2034 (inhibitor of glycinamid ribonucleotide formyltransferase), and pemetrexed (inhibits both of the above enzymes plus thymidylate synthase, TS) all result in the increase of p21 levels. [24][25][26][27] These drugs target folate metabolism, ultimately inhibiting de novo purine and TMP biosynthesis. It has been also reported that sensitivity to 5-FU, another TS inhibitor, was increased in cells upon elevation of p21 levels.…”

Section: Introductionmentioning

confidence: 99%

Activation of p21-Dependent G1/G2 Arrest in the Absence of DNA Damage as an Antiapoptotic Response to Metabolic Stress

et al. 2011

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The folate enzyme, FDH (10-formyltetrahydrofolate dehydrogenase, ALDH1L1), a metabolic regulator of proliferation, activates p53-dependent G1 arrest and apoptosis in A549 cells. In the present study, we have demonstrated that FDH-induced apoptosis is abrogated upon siRNA knockdown of the p53 downstream target PUMA. Conversely, siRNA knockdown of p21 eliminated FDH-dependent G1 arrest and resulted in an early apoptosis onset. The acceleration of FDH-dependent apoptosis was even more profound in another cell line, HCT116, in which the p21 gene was silenced through homologous recombination (p21 -/-cells). In contrast to A549 cells, FDH caused G2 instead of G1 arrest in HCT116 p21 +/+ cells; such an arrest was not seen in p21-deficient (HCT116 p21 -/-) cells. In agreement with the cell cycle regulatory function of p21, its strong accumulation in nuclei was seen upon FDH expression. Interestingly, our study did not reveal DNA damage upon FDH elevation in either cell line, as judged by comet assay and the evaluation of histone H2AX phosphorylation. In both A549 and HCT116 cell lines, FDH induced a strong decrease in the intracellular ATP pool (2-fold and 30-fold, respectively), an indication of a decrease in de novo purine biosynthesis as we previously reported. The underlying mechanism for the drop in ATP was the strong decrease in intracellular 10-formyltetrahydrofolate, a substrate in two reactions of the de novo purine pathway. Overall, we have demonstrated that p21 can activate G1 or G2 arrest in the absence of DNA damage as a response to metabolite deprivation. In the case of FDH-related metabolic alterations, this response delays apoptosis but is not sufficient to prevent cell death.

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Genetic Determinants of Pemetrexed Responsiveness and Nonresponsiveness in Non-small Cell Lung Cancer Cells

Abstract: Our results indicated that downregulation of TS and DHFR genes and upregulation of p21, p27, Lcn-2, and nm23-H1 genes may serve as new biomarkers for predicting responsiveness to pemetrexed.

Cited by 41 publications

References 27 publications

The Pemetrexed-Containing Treatments in the Non-small Cell Lung Cancer, Is -/Low Thymidylate Synthase Expression Better than +/High Thymidylate Synthase Expression? A Meta-analysis

The Pemetrexed-Containing Treatments in the Non-small Cell Lung Cancer, Is -/Low Thymidylate Synthase Expression Better than +/High Thymidylate Synthase Expression? A Meta-analysis

Inhibition of dUTPase Induces Synthetic Lethality with Thymidylate Synthase–Targeted Therapies in Non–Small Cell Lung Cancer

Activation of p21-Dependent G1/G2 Arrest in the Absence of DNA Damage as an Antiapoptotic Response to Metabolic Stress

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